Efficient blending and sampling of powders is of critical importance in the manufacture of a wide variety of pharmaceutical solid doses such as tablets and capsules. These products are manufactured from powder blends, granulated powders, and extruded pellets. In a typical process, powders, granules, and pellets are blended, discharged to a tote or drum, emptied into a hopper on a press or encapsulator, and divided into the final dosage form. Achieving and maintaining homogeneous and well characterized blends of powders and granules is of critical importance, especially in formulations involving small amounts of high potency components, which are a substantial fraction of all oral dosages. Inadequate mixing somewhere along the production sequence often results in rejection of finished product due to poor quality.
In many systems, the components requiring blending are usually powders of different size, density, shape, and cohesiveness. Since such materials often display a considerable tendency to segregate, ultimate mixture homogeneity cannot be taken for granted; quite the opposite, unless the blending process is properly designed and controlled, the result is often a mixture with significant composition fluctuations throughout the powder bed [See, L. T. Fan, Y.-M. Chen, and F. S. Lai, Powder Technol., 61 (1990) 255. and M. Poux, P. Fayolle, J. Bertrand, D. Bridoux, and J. Bousquet, Powder Technol., 68 (1991) 213.]. Inhomogeneities in the powder blend can result in increased variability in the contents of potent components in tablets, leading not only to decreased therapeutic value but also to direct health risks due to toxicity in super-potent tablets.
For the reasons mentioned above, a thorough understanding of blending processes is highly desirable. Unfortunately, blending of granular materials is largely an art rather than a science, and at the present time the ability to design and accurately evaluate the performance of a mixing process for a high potency drug is limited.
Characterization of mixtures in most industrial processes relies on taking and analyzing discrete samples. Parameters such as sample size (n), number of samples (N), and location of the sampling points can affect the measurement values. Guidelines for selecting the number of samples have been proposed based on theoretical random mixtures (i.e., &gt;30) [Devore, J. L., Probability and Statistics for Engineering and the Sciences, Vol., Brooks/Cole Publishing Company, Monterey, 1982, p. 640] but optimal values of these parameters for real systems displaying incomplete mixing are often unknown.
In real mixtures, practical considerations and physical limitations of sampling mechanisms limit the number and size of the samples that can be obtained. Extensive sampling is often impractical; commonly, just a few samples (&lt;30) are removed from a blender. The most common approach is to use a thief probe to withdraw samples from different locations in stationary powder mixtures.
Of signifcant interest are two essential sampling problems that cannot be easily solved using currently available commercial technology:
(i) Disturbances. The most common technique for obtaining samples is to use a thief probe. Available probes can introduce large errors in sample composition due to the massive disturbances that take place during insertion of the probe. PA1 (ii) Segregation. It is well known among practitioners that powder mixtures can segregate (unmix) upon handling. Segregation can be a major sampling problem in any sampling process involving dry powders because such powders often segregate during insertion of the thief.
Thief samplers belong to two main classes: side sampling and end sampling. A typical side sampling probe has one or more cavities drilled or stamped in an inner cylinder enclosed by an outer rotating sleeve. The sleeve has holes that align with the cavities, allowing adjacent powder to flow into the cavities. Rotating the sleeve to its closed position traps the particles into the cavities. An end sampling thief has a single cavity at the end of the probe that can be remotely opened and closed. In both cases, the thief is introduced into the powder with its cavities closed. Once insertion is complete, the cavities are opened, allowing the powder to flow into them. The cavities are then closed, and thief is withdrawn, removing samples from the mixtures.
Thief sampling is a rather laborious and cumbersome technique and it is rarely practical to take more than 10 or 20 samples. In any sampling scheme, the experimentally measured variance, .sigma..sub.e.sup.2, is actually a combination of the true variance resulting from the mixing process, .sigma..sub.m.sup.2, the variance introduced by sampling error, .sigma..sub.s.sup.2 [Fan, L. T., et al., Powder Technol., 61 (1990) 255], and the variance resulting from analytical analysis, .sigma..sub.a.sup.2, i.e., EQU .sigma..sub.e.sup.2 =.sigma..sub.m.sup.2 +.sigma..sub.s.sup.2 +.sigma..sub.a.sup.2 (1)
In an ideal situation, .sigma..sub.s.sup.2 and .sigma..sub.a.sup.2 are negligible, and .sigma..sub.e.sup.2 (the variance subject to USP rules) is almost identical to .sigma..sub.m.sup.2 (the true variance). Unfortunately, thief probes bias measurements to the point that sampling uncertainty is expected to be a large fraction of the measurement [Ashton, M. D., et al., Trans. Instn. Chem. Engrs., 44 (1966) T166; Schofield, C., Powder Technol., 15 (1976) 169; Yip, C.W., et al., Powder Technol., 16 (1977) 189; Lai, F., et al., Chem. Eng. Sci., 36 (1981) 1133]. As mentioned earlier, two type of errors are often introduced by thief probes: (i) the mixture is extensively disturbed when the thief probe is inserted into the powder bed, and (ii) particles of different sizes often flow unevenly into the thief cavities. Side-sampling probes often have an additional problem: cohesive powders do not flow easily into thief cavities, sometimes resulting in samples that are smaller than desired.
Only a few studies have attempted to quantify the errors introduced by thief probes mainly focusing on side-sampling thief probes [Carley-Macauly, K. W., et al., Chem. Eng. Sci., 17 (1962) 493; Schofield, C., Powder Technol., 15 (1976) 169; Poole, K. R., et al., Trans. Instn. Chem. Engrs., 42 (1964) T305; Masiuk, S., Powder Technol., 51 (1987) 217; Gopinath, S., 27 (1982) 321; Gayle, J. B. et al., 50 (1958) 1279]. Carley-Macauley and Donald [Carley-Macauly, K. W., et al., Chem. Eng. Sci., 17 (1961) 493] performed a comparison study between two types of side sampling probes. One was a conventional probe (as described above); the other probe had cavities that were closed using a longitudinal slit. They took samples from a system composed of sand of two colors arranged in a layered structure. The conventional probe gave samples of a mixed color within a region of two aperture diameters (0.13") from the layer boundary. In the longitudinal slit probe, sand particles tended to run down the slit, causing errors greater than the conventional side sampling probe. In both cases, errors occur because the probe is sampling locations that have already been disturbed by the insertion of the probe itself. Other studies have reached similar conclusions. For example, in a study conducted by Williams and Khan [Williams, J. C., et al., Chem. Eng., (1973) 19], although no quantitative data was reported, the authors concluded that a side sampling thief gave totally misleading results in a segregating system. Instead, they used a sampler that removed a core of powder from the bed. The sampler was divided into sections in order to divide the core into samples. Orr and Shotton [Orr, N. A., et al., Chem. Eng., London, January (1973)12] determined that perturbations of the mixture structure are caused by friction along the length of the probe, and are independent of the profile of the tip. This result suggests that an end sampling probe will perform better than a side sampling probe because for an end-sampling probe the sample is taken from a relatively undisturbed region of powder beneath the tip of the probe. They developed such a probe for use with cohesive powders. Components sampled at depths of 1, 2, 4 and 6 cm through a 2 cm layer of charcoal powder qualitatively showed little contamination of the samples with charcoal powder. In a quantitative analysis, 20 samples of cohesive calcium carbonate were taken through a layer of cohesive lactose at a depth of 2 cm below an interface. The maximum amount of lactose found in the samples was 0.07% [Orr, N. A., et al., Chem. Eng., London, January (1973)12].